Ophthalmic emulsion

ABSTRACT

The present invention is directed to an ophthalmic emulsion. The emulsion has a unique combination of ingredients that promotes the stability of small oil droplets within the emulsion. The emulsion also includes a mucoadhesive polymer that aid in delivering a lipid to the ocular surface.

This application is a continuation of U.S. patent application Ser. No.15/228,589 filed Aug. 4, 2016; which is a continuation of U.S. patentapplication Ser. No. 12/958,763 filed Dec. 2, 2010, now abandoned; whichapplication claimed priority to provisional application Ser. No.61/266,207, filed Dec. 3, 2009.

TECHNICAL FIELD OF THE INVENTION

The present invention is directed to an ophthalmic emulsion. Moreparticularly, the present invention is directed to an ophthalmicemulsion having a unique combination of ingredients that promotes thestability of small oil droplets within the emulsion and promotes thetherapeutic delivery capability of the emulsion.

BACKGROUND OF THE INVENTION

There are a variety of types of ophthalmic compositions such as aqueoussolutions, aqueous suspensions and others. Ophthalmic compositions areoccasionally formulated as emulsions. Ophthalmic emulsions are typicallyemployed in circumstances where it is desirable to include two or moreingredients that are immiscible relative to each other in a singlecomposition and therefore form two separate phases within thecomposition. Such emulsions can allow a single composition to providethe advantages attributable to both phases (e.g., advantageous deliverycharacteristics). For example, an emulsion can be formed of oil dropletsin an aqueous phase where the oil droplets can be used as carriers foractives such as therapeutic agents (e.g., drugs) or excipients whichhave poor solubility and/or stability in water.

Examples of emulsions are included in U.S. Pat. Nos. 4,914,088;5,278,151; 5,294,607; 5,371,108; and 5,578,586. Each of these patents isincorporated herein by reference for all purposes.

It is typically quite desirable for one phase of an emulsion to besubstantially uniformly dispersed within the other phase. Suchdispersion can significantly effect the capabilities of emulsion todeliver therapeutic ingredients. Moreover, such dispersion is often anindication of the stability of the emulsion itself.

The separate phases of an emulsion can be extremely difficult to evenlydisperse throughout a composition since each phase tends to associatewith itself rather than the other phase. Thus, the maintenance of thedistribution of one phase (i.e., the dispersed phase) within the otherphase (i.e., the continuous phase) can be very delicate. Moreover, it isalso often difficult to include additional ingredients within anemulsion since many ingredients can act to inhibit the dispersion and/oreven distribution of the dispersed phase throughout the continuousphase.

The emulsions of the present invention are two phase systems comprisingof oil droplets dispersed in water. The size of the droplets istypically less than 1000 nm but typically greater than 10 nm.Accomplishing such droplet size is difficult since emulsions aretypically thermodynamically or otherwise unstable and require one ormore excipients to impart stability to the emulsion and prevent the oildroplets from coalescing. De-emulsification of the emulsions needs to bekinetically hindered particularly under exacerbated conditions such asstorage of the emulsion at high ambient temperatures (e.g., warehousesduring summer months, especially in tropical or central continental orMediterranean climates, or by a temperature cycle in which theformulations are subjected to cyclical heating and cooling).Additionally, the presence of high ionic strengths in the aqueous phasecan lead to de-emulsification.

While small droplet size is difficult to maintain for a simple emulsion,droplet size maintenance can be substantially more complicated whenadditional ingredients are included in the emulsion (see Surfaceproperties and emulsification activity of galactomannans, FoodHydrocolloids, Volume 8, Issue 2, May 1994, Pages 155-173 Nissim Garti,Dov Reichman). For ophthalmic emulsions, it can be particularlydifficult to integrate mucoadhesive materials, particularly mucoadhesivepolymers, into the emulsion without causing undesirable instability inemulsion oil droplet size. It would be desirable to provide an emulsionthat can maintain small droplets and it would be particularly desirableto be able to maintain small droplets in the presence of a mucoadhesivepolymer.

Accordingly, there is a need for a method that is capable of producingstable emulsions containing a mucoadhesive polymer. Additionally oralternatively, there remains an outstanding desire for aqueous emulsionswhich have shear thinning properties to be effective for lubricating andprotecting the cornea (dry eye patients). Alternatively or additionally,there remains a need for a method or an alternative method to produce anemulsion comprising a fine dispersion of oil droplets that is preservedwith an antimicrobial compound, and particularly a process to produce astable preserved emulsion.

OBJECTS OF THE INVENTION

It is an object of at least one aspect of the present invention toprovide a process that is capable producing a stable emulsion having asmall mean droplet in the presence of a mucoadhesive polymer.

It is an object of at least one aspect of the present invention toprovide an emulsion which is resistant to phase separation, andparticularly offering resistance to phase separation during storage atabove standard temperatures and heating/cooling cycling conditions.

SUMMARY OF THE INVENTION

The present invention is directed to an ophthalmic emulsion thatincludes the following: water forming an aqueous phase; oil forming anoil phase; a hydrophilic surfactant; a hydrophobic surfactant; a chargedphospholipid; borate; and a mucoadhesive polymer (e.g., a galactomannanpolymer). The oil phase is in droplets within the aqueous phase and thedroplets have an average or mean diameter no greater than about 1500nanometers (nm), more typically no greater than about 1000 nm and stillmore typically no greater than about 500 nm. These droplets alsotypically have an average or mean diameter of at least 2 nm, moretypically at least 10 nm and still more typically at least 100 nm. Theborate and galactomannan polymer cooperatively act to form a gel uponinstillation of the emulsion in an eye of an individual.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is predicated upon the provision of an ophthalmicoil in water emulsion wherein the emulsion has average oil droplet sizethat is relatively small. The emulsion will typically be aqueous andinclude a substantial amount of water. The emulsion will also typicallyinclude an anionic phospholipid, a hydrophilic surfactant (high HLB) anda hydrophobic (low HLB) surfactant. Further, the emulsion will typicallyinclude one or more mucoadhesive ingredients (e.g., galactomannanpolymers) to aid in maintaining the emulsion on the corneal surface ofthe eye and/or aid in delivering one or more lipophilic compounds to thecorneal surface. The emulsions of the present invention are mostdesirably used for dry eye therapeutics. However, without limitation, itis also contemplated that the emulsions may be used for drug delivery,vitamin delivery, botanical delivery, contact lens wetting and contactlens lubrication.

Unless otherwise specifically stated all emulsion ingredient amounts orpercentages are weight volume percentages (w/v %).

The oil of the emulsion is dispersed throughout the continuous water oraqueous phase as small droplets that are substantially distinct andseparate. It should be understood that, as used herein, the phasedistinct and separate means that, at any give point in time, thedroplets are distinct and separate. However, the droplets of theemulsion can combine and separate over time to maintain an averagedroplet size or diameter. The droplets of the emulsion of the presentinvention typically have an average or mean diameter no greater thanabout 1500 nanometers (nm), more typically no greater than about 1000 nmand still more typically no greater than about 600 nm. These dropletsalso typically have an average or mean diameter that is typically atleast 2 nm, more typically at least 10 nm and still more typically atleast 100 nm.

Particle or droplet size analyzers may be used to determine emulsion oildroplet size. For example, a Microtrac S3500 Particle Size Analyzer(Software Version 10.3.1) is a tri-laser particle size analyzer that canbe used to measure emulsion oil droplet size. That particular analyzermeasures laser light diffracted (scattered) from particles (e.g.,droplets) in a flowing stream. The intensity and direction of thescattered light is measured by two optical detectors. Mathematicalanalysis of the diffraction pattern by the software generates a volumedistribution of droplet size. The droplet diameter corresponding to 90%of the cumulative undersize distribution by volume is used.

The emulsion of the present invention is an oil in water emulsion. Theoil can be any of numerous mineral, vegetable, and synthetic substancesand/or animal and vegetable fats or any combination of oils. The oil canbe soluble in various organic solvents such as ether but not in water.The oil phase can comprise, if desired a liquid hydrocarbon, such as amineral oil, paraffin oils, petrolatum or hydrocarbon oils. Mineral oilis particularly preferred. A silicone oil may also be used. The oilphase can additionally include a waxy hydrocarbon, such as paraffinwaxes, hydrogenated castor oil, Synchrowax HRC, Carnabau, beeswax,modified beeswaxes, microcrystalline waxes, and polyethylene waxes. Theoil is typically at least 0.01 w/v %, more typically at least 0.1 w/v %and even more typically 0.8 w/v % of the emulsion. The oil is alsotypically no greater than about 20 w/v %, more typically no greater thanabout 5 w/v % and even more typically no greater than about 3 or even1.5 w/v % of the emulsion

The emulsion of the present invention also typically incorporates two ormore surfactants, which act as emulsifiers aiding in the emulsificationof the emulsion. Typically, these surfactants are non-ionic. Theconcentration of emulsifying surfactant in the emulsion is oftenselected in the range of from 0.1 to 10% w/v, and in many instances from0.5 to 5% w/v. It is preferred to select at least oneemulsifier/surfactant which is hydrophilic and has an HLB value of atleast 8 and often at least 10 (e.g., 10 to 18). It is further preferredto select at least one emulsifier/surfactant which is hydrophobic andhas an HLB value of below 8 and particularly from 1 to 6. By employingthe two surfactants/emulsifiers together in appropriate ratios, it isreadily feasible to attain a weighted average HLB value that promotesthe formation of an emulsion. For most emulsions according to thepresent invention, the average HLB value is chosen in the range of about6 to 12, and for many from 7 to 11.

For example.

For example, the HLB values for exemplary surfactants and mineral oilare as follows: hydrophobic surfactant (2.1), hydrophilic surfactant(16.9) and mineral oil (10.5). The concentrations of hydrophobicsurfactant and hydrophilic surfactant used in exemplary emulsions were0.38% and 0.29% based on these calculations.

.29/.67 = 0.43  and  .38/.67 = 0.57 $\begin{matrix}{{hydrophobic}\mspace{14mu} {surfactant}} & {{2.1 \times 0.43} = 0.90} \\{{hydrophilic}\mspace{14mu} {surfactant}} & {{16.9 \times 0.57} = \underset{\_}{9.63}} \\\; & 10.53\end{matrix}$

The ratio between hydrophobic surfactant and hydrophilic surfactant isequal to 1.32 which can be used to select the proper ratio ofconcentrations to be used for the two surfactants. The concentrations ofhydrophobic surfactant and hydrophilic surfactant used in exemplaryemulsions were 0.38% and 0.29% based on these calculations.

The hydrophilic surfactant is typically present in the emulsion in anamount that is at least about 0.01 w/v %, more typically at least about0.08 w/v % and even more typically at least about 0.14 w/v %. Thehydrophilic surfactant is typically present in the emulsion in an amountthat is no greater than about 1.5 w/v %, more typically no greater thanabout 0.8 w/v % and even more typically no greater than about 0.44 w/v%.

The hydrophilic surfactant can be a fatty acid, an ester, an ether, anacid or any combination thereof. The hydrophilic surfactant may be ionicor non-ionic, but is preferably non-ionic. Many suitablesurfactants/emulsifiers are nonionic ester or ether emulsifierscomprising a polyoxyalkylene moiety, especially a polyoxyethylenemoiety, often containing from about 2 to 80, and especially 5 to 60oxyethylene units, and/or contain a polyhydroxy compound such asglycerol or sorbitol or other alditols as hydrophilic moiety. Thehydrophilic moiety can contain polyoxypropylene. The emulsifiersadditionally contain a hydrophobic alkyl, alkenyl or aralkyl moiety,normally containing from about 8 to 50 carbons and particularly from 10to 30 carbons. Examples of hydrophilic surfactants/emulsifiers includeceteareth-10 to-25, ceteth-10-25, steareth-10-25, and PEG-15-25 stearateor distearate. Other suitable examples include C10-C20 fatty acid mono,di or tri-glycerides. Further examples include C18-C22 fatty alcoholethers of polyethylene oxides (8 to 12 EO). One particularly preferredhydrophilic surfactant is polyoxyethylene-40-stearate, which is soldunder the tradename MYRJ-52, which is commercially available from NikkoChemicals.

The hydrophobic surfactant is typically present in the emulsion in anamount that is at least about 0.01 w/v %, more typically at least about0.11 w/v % and even more typically at least about 0.16 w/v %. Thehydrophobic surfactant is typically present in the emulsion in an amountthat is no greater than about 10.0 w/v %, more typically no greater thanabout 2.0 w/v % and even more typically no greater than about 0.62 w/v%.

The hydrophobic surfactant can be a fatty acid, an ester, an ether, anacid or any combination thereof. The hydrophobic surfactant may be ionicor non-ionic, but is preferably non-ionic. The hydrophobic surfactantwill typically include a hydrophobic moiety. The hydrophobic moiety canbe either linear or branched and is often saturated, though it can beunsaturated, and is optionally fluorinated. The hydrophobic moiety cancomprise a mixture of chain lengths, for example those deriving fromtallow, lard, palm oil sunflower seed oil or soya bean oil. Suchnon-ionic surfactants can also be derived from a polyhydroxy compoundsuch as glycerol or sorbitol or other alditols. Examples of hydrophobicsurfactants include, without limitation, sorbitan fatty acid esters suchas sorbitan monoleate, sorbitan monostearate, sorbitan monolaurate,sorbitan monopalmitate, sorbitan monoisostearate, sorbitan trioleate,sorbitan tristearate, sorbitan sesquioleate, sorbitan sesquistearate,combinations thereof or the like. One particularly preferred hydrophobicsurfactant is a sorbitan tristearate sold under the tradename SPAN-65,which is commercially available from Croda Worldwide.

The types of galactomannans that may be used in the present inventionare typically derived from guar gum, locust bean gum and tara gum. Asused herein, the term “galactomannan” refers to polysaccharides derivedfrom the above natural gums or similar natural or synthetic gumscontaining mannose or galactose moieties, or both groups, as the mainstructural components. Preferred galactomannans of the present inventionare made up of linear chains of (1-4)-.beta.-D-mannopyranosyl units with.alpha.-D-galactopyranosyl units attached by (1-6) linkages. With thepreferred galactomannans, the ratio of D-galactose to D-mannose varies,but generally will be from about 1:2 to 1:4. Galactomannans having aD-galactose:D-mannose ratio of about 1:2 are most preferred.Additionally, other chemically modified variations of thepolysaccharides are also included in the “galactomannan” definition. Forexample, hydroxyethyl, hydroxypropyl and carboxymethylhydroxypropylsubstitutions may be made to the galactomannans of the presentinvention. Non-ionic variations to the galactomannans, such as thosecontaining alkoxy and alkyl (C1-C6) groups are particularly preferredwhen a soft gel is desired (e.g., hydroxylpropyl substitutions).Substitutions in the non-cis hydroxyl positions are most preferred. Anexample of non-ionic substitution of a galactomannan of the presentinvention is hydroxypropyl guar, with a molar substitution of about 0.4.Anionic substitutions may also be made to the galactomannans. Anionicsubstitution is particularly preferred when strongly responsive gels aredesired. A galactomannan is typically present in a formulation of thepresent invention at a concentration of at least about 0.005 w/v %, moretypically at least about 0.01 w/v % and even more typically at leastabout 0.03 w/v %, but typically no greater than about 5 w/v %, moretypically no greater than about 1.0 w/v %, still more typically nogreater than about 0.3 w/v % and even still more typically no greaterthan about 0.08 w/v %. Preferred galactomannans of the present inventionare guar and hydroxypropyl guar.

The emulsion may include additional or alternative polymeric ingredientsand/or viscosity agents. Examples include, without limitation,carboxymethylcellulose, hydroxypropylmethyl cellulose, hydroxyethylcellulose, carboxyvinyl polymer, xanthan gum, hyaluronic acid, anycombinations thereof or the like.

The emulsion of the present invention includes at least one phospholipidfor aiding in maintaining the stability of the emulsion and for reducingdroplet size of the oil. It is known that complex phospholipids cancontain a polar group at one end of their molecular structure and anon-polar group at the opposite end of their molecular structure. Adiscussion of phospholipids can be found in Lehninger, Biochemistry, 2ed., Worth Publishers, New York, pp. 279-306, incorporated herein byreference for all purposes.

Many complex phospholipids are known to the art. They differ in size,shape and the electric charge of their polar head groups.Phosphoglycerides are compounds where one primary hydroxyl group ofglycerol is esterified to phosphoric acid, and the other two hydroxylgroups are esterified with fatty acids. The parent compound of theseries is, therefore, the phosphoric acid ester of glycerol. Thiscompound has an asymmetric carbon atom and, therefore, the termphosphoglycerides includes stereoisomers. All phosphoglycerides have anegative charge at the phosphate group at pH 7, and the pK_(a) of thisgroup is in the range of 1 to 2. The head groups ofphosphatidylinositol, phosphatidylglycerol includingdiphosphatidylglycerols (having the common name cardiolipins) and thephosphatidylsugars have no electric charge, and all are polar because oftheir high hydroxyl group content. Because of the negative charge of thephosphate group and the absence of a charge in the head group, the netcharge of each of these materials is negative, and these materials arewithin the scope of the invention. Suitable phospholipids are thosecarrying a net positive or negative charge under conditions of use. Thepreferred materials are those carrying a net negative charge because thenegatively charged material will be repelled by the negatively chargedocular surface thereby permitting the maintenance of a relatively thickaqueous layer upon application to the eye. The most preferredphospholipid is an anionic phospholipid named dimyristoylphosphatidylglycerol (DMPG), which is a polyol with a net negativecharge. Phosphatidylglycerol or a phosphatidylinositol are otherexamples. Suitable phospholipid additives are disclosed in the abovecited U.S. Pat. No. 4,914,088, which is fully incorporated herein byreference for all purposes.

Most phospholipids are water insoluble. However, for application to theeye, it is desirable that the phospholipid be homogeneously distributedthroughout an aqueous medium. For those few phospholipids having asolubility within a useful concentration range for use as a treatmentcomposition, a simple aqueous solution of the phospholipid in saline issatisfactory. For those phospholipids that are essentially waterinsoluble, an aqueous composition in the form of an emulsion may beused. An emulsion provides a treatment composition where the phasecontaining the phospholipid component is homogeneously distributedthroughout the aqueous vehicle.

The concentration of the phospholipid in the treatment composition mayvary within wide limits. A treatment composition containing the complexphospholipid in an amount as low as 0.01 weight percent provides somebenefit. When the treatment composition is in the form of an emulsion,compositions containing the phospholipid in elevated concentrationsapproaching collapse of the emulsion into separate aqueous andphospholipid phases is possible. A clinically practical concentrationrange for the phospholipid in its vehicle varies from about 0.05 to 7.0w/v % phospholipid by weight, and more preferably varies from about 0.1and 5.0 w/v %. It should be noted that the most desired concentrationfor the phospholipid in the aqueous composition will vary from subjectto subject.

Other additives may be present in the phospholipid treatment compositionincluding neutral lipids such as one or more triglycerides, cholesterolesters, the natural waxes and cholesterol; higher molecular weightisoprenoids; stabilizers; preservatives; pH adjustors to provide acomposition preferably having a pH between about 6 and 8 and morepreferably between about 7.0 and 7.4; salt in sufficient concentrationto form an isotonic composition; medicants; etc.

As indicated above, the emulsions of the present invention can includeborate or borate/polyol buffer systems. As used herein, the term“borate” includes boric acid, salts of boric acid, otherpharmaceutically acceptable borates, and combinations thereof. Thefollowing borates are particularly preferred: boric acid, sodium borate,potassium borate, calcium borate, magnesium borate, manganese borate,and other such borate salts.

As used herein, the term “polyol” includes any compound having at leastone hydroxyl group on each of two adjacent carbon atoms that are not intrans configuration relative to each other. The polyols can be linear orcyclic, substituted or unsubstituted, or mixtures thereof, so long asthe resultant complex is water soluble and pharmaceutically acceptable.Examples of such compounds include: sugars, sugar alcohols, sugar acidsand uronic acids. Preferred polyols are sugars, sugar alcohols and sugaracids, including, but not limited to: mannitol, glycerin, xylitol andsorbitol. Especially preferred polyols are mannitol and sorbitol; mostpreferred is sorbitol.

The use of borate-polyol complexes in ophthalmic compositions isdescribed in U.S. Pat. No. 6,503,497 (Chowhan); the entire contents ofwhich are hereby incorporated in the present specification by reference.The emulsions of the present invention preferably contain one or moreborates in a concentration that is at least about 0.01% w/v, moretypically at least about 0.3% w/v and even more typically at least about0.8% w/v, but typically no greater than about 5.0% w/v, more typicallyno greater than about 2.0% w/v and even more typically no greater thanabout 1.2% w/v. It is generally desirable for the amount of the one ormore borates to be sufficient to allow the formation of borate/polyolcomplexes and, when desired, to aid in gelling the galactomannan polymerupon application of the emulsion to the eye.

The compositions of the present invention typically include apreservative. Potential preservatives include, without limitation,hydrogen peroxide, chlorine containing preservatives such asbenzalkonium chloride or others. According to a preferred aspect,however, the ophthalmic composition of the present invention issubstantially free of any chloride containing preservatives and,particularly, is substantially free of benzalkonium chloride. Mostpreferred preservatives included in the ophthalmic composition arepolymeric quaternary ammonium compounds.

As used herein, the phrase “substantially free of” as it refers to aningredient of the ophthalmic composition means that it is contemplatedthat the ophthalmic solution can be either entirely devoid of thatparticular ingredient or includes only a nominal amount of thatparticular ingredient.

The polymeric quaternary ammonium compounds useful in the compositionsof the present invention are those which have an antimicrobial effectand which are ophthalmically acceptable. Preferred compounds of thistype are described in U.S. Pat. Nos. 3,931,319; 4,027,020; 4,407,791;4,525,346; 4,836,986; 5,037,647 and 5,300,287; and PCT application WO91/09523 (Dziabo et al.). The most preferred polymeric ammonium compoundis polyquaternium 1, otherwise known as POLYQUAD® or ONAMERM® with anumber average molecular weight between 2,000 to 30,000. Preferably, thenumber average molecular weight is between 3,000 to 14,000.

The polymeric quaternary ammonium compounds are generally used in thecompositions of the present invention in an amount that is greater thanabout 0.00001 w/v %, more typically greater than about 0.0003 w/v % andeven more typically greater than about 0.0007 w/v % of the ophthalmiccomposition. Moreover, the polymeric quaternary ammonium compounds aregenerally used in the compositions of the present invention in an amountthat is less than about 3 w/v %, more typically less than about 0.003w/v % and even more typically less than about 0.0015 w/v % of theophthalmic composition.

The emulsion of the present invention can include any of a multitude ofophthalmic therapeutic agents. Non-limiting examples of potentialophthalmic therapeutic agents for the present invention include:anti-glaucoma agents, anti-angiogenesis agents; anti-infective agents;anti-inflammatory agents; growth factors; immunosuppressant agents; andanti-allergic agents. Anti-glaucoma agents include beta-blockers, suchas betaxolol and levobetaxolol; carbonic anhydrase inhibitors, such asbrinzolamide and dorzolamide; prostaglandins, such as travoprost,bimatoprost, and latanoprost; seretonergics; muscarinics; dopaminergicagonists. Anti-angiogenesis agents include anecortave acetate (RETAANE™,Alcon™ Laboratories, Inc. of Fort Worth, Tex.) and receptor tyrosinekinase inhibitors (RTKi). Anti-inflammatory agents include non-steroidaland steroidal anti-inflammatory agents, such as triamcinolone actinide,suprofen, diclofenac, ketorolac, nepafenac, rimexolone, andtetrahydrocortisol. Growth factors include EGF or VEGF. Anti-allergicagents include olopatadine and epinastine. The ophthalmic drug may bepresent in the form of a pharmaceutically acceptable salt.

The present invention can be particularly useful for deliverytherapeutic agents that relieve symptoms of dry eye conditions. Examplesinclude, without limitation, steroidal and/or non-steroidalanti-inflammatory agents; selective PDE IV inhibitors such ascilomilast, cyclosporins, combinations thereof or the like. The emulsionof the invention can also be used in other fields, such as to delivercooling agents, deliver antioxidants (omega-3 and omega-6 fatty acids)and other bioactivies for ophthalmic uses. For example, nutriceuticalssuch as vitamin A (retinol), vitamin D (calciferol), vitamin E,tocopherols, vitamin K (quinone), beta-carotene (pro-vitamin-A) andcombinations thereof.

Generally, amounts of therapeutic agent, when used, can be quitevariable depending upon the agent or agents used. As such, theconcentration of therapeutic agent can be at least about 0.005 w/v %,more typically at least about 0.01 w/v % and even more typically atleast about 0.1 w/v %, but typically no greater than about 10 w/v %,more typically no greater than about 4.0 w/v %, still more typically nogreater than about 2.0 w/v %.

The emulsions of the present invention may optionally comprise one ormore additional excipients and/or one or more additional activeingredients. Excipients potentially used in the ophthalmic emulsionsinclude, but are not limited to, demulcents, tonicity agents,preservatives, chelating agents, buffering agents, and surfactants.Other excipients comprise solubilizing agents, stabilizing agents,comfort-enhancing agents, polymers, emollients, pH-adjusting agentsand/or lubricants.

The emulsion is typically aqueous and therefore includes a substantialamount of water, which is typically purified. The emulsion typicallyincludes water at a concentration of at least about 50 w/v %, moretypically at least about 85 w/v % and even more typically at least about93 w/v %, but typically no greater than about 99.99 w/v %, moretypically no greater than about 99.0 w/v %, still more typically nogreater than about 0.3 w/v % and even still more typically no greaterthan about 98 w/v %.

The emulsion of the present invention may be formed using a variety ofcombining and mixing protocol and techniques known to those skilled inthe art. According to one preferred embodiment, however, the ingredientsare mixed and combined according to a specific protocol. In suchprotocol, multiple admixtures are formed and those admixtures arecombined to form the emulsion. The first admixture is formed by mixingthe oil and the surfactants at an elevated temperature to form an oilphase admixture. The second admixture is formed mixing the anionicphospholipid into purified water at an elevated temperature to form awater phase admixture. Thereafter, the oil phase admixture and the waterphase admixture are mixed at an elevated temperature and subsequentlyhomogenized using a homogenizer to form an initial emulsion. A thirdadmixture is formed by mixing the galactomannan polymer with water andadjusting pH as needed to form a galactomannan polymer slurry. Thegalactomannan polymer slurry is then mixed with initial emulsion andform a polymer enhanced emulsion. A fourth admixture is formed by mixingany combination of the following to form a salt solution: borate,polyol, preservative and any other ingredients. The salt solution andthe enhanced emulsion are then mixed followed by the addition of asufficient quantity (Q.S.) of water and pH adjustment.

The emulsion can be used as an ocular lubricant, a drug delivery vehicleor the like. However, it has been found particularly desirable for useas a dry eye therapy. As such, a individual diagnosed with orexperiencing dry eye symptoms can dispense the emulsion to thatindividual's eye for alleviating those dry eye symptoms. Typically theemulsion is provided in an eye dropper such that an individual mayinstill one, two or more drops into one or both of their eyes on aregular or as needed basis. Upon instillation, the emulsion willtypically gel upon the corneal surface of the eye allowing for moresignificant therapeutic effects such as aiding in the delivery of lipidsto the ocular surface.

Advantageously, the stability of the oil in water emulsion of thepresent invention can facilitate lubrication and/or the delivery oflipids (e.g., lipid therapeutic agents) to the ocular surface. Theselipids can aid in stabilizing the tear film and/or can providealternative therapeutic advantages to the eye. Moreover, themucoadhesive polymer can aid residence time of the emulsions upon theeye such that the emulsions can be more efficacious.

Examples

TABLE I CONCENTRATION COMPONENT PERCENT, W/V Polyquatemium-1 0.001 +10%* HP-Guar 0.05  Mineral oil 1.0  Boric Acid 1.0  Anionic Phospholipid0.005 Polyoxyl 40 Stearate 0.38  Sorbitan Tristearate 0.29  PropyleneGlycol 0.6  Sorbitol 0.7  Edetate Disodium 0.025 Sodium Hydroxide AdjustpH to 7.0 Hydrochloric Acid Adjust pH to 7.0 Purified Water QS 100

Table 1 above is a formulation for one exemplary emulsion in accordancewith the present invention. It is understood that the weight/volumepercents in table I can be varied by ±10%, ±20%, ±30%, ±90% of thoseweight/volume percents or more and that those variances can bespecifically used to create ranges for the ingredients of the presentinvention. For example, an ingredient weight/volume percent of 10% witha variance of ±20% means that the ingredient can have a weight/volumepercentage range of 8 to 12 w/v %.

TABLE II Typical Concentration range Components for testingPolyquaternium-1       0-0.001% Mineral Oil 1   HP-Guar 0.05-0.18polyoxyl-40 stearate 0.19-0.38 Sorbitan tristearate 0.15-0.29 AnionicPhospholipid   0-0.1 Boric Acid 1.0 Sorbitol 0.7 Propylene Glycol 0.6ZnCl₂    0-0.0015

Table 2 above is a formulation for one exemplary emulsion in accordancewith the present invention. It is understood that the weight/volumepercents in table I can be varied by ±10%, ±20%, ±30%, ±90% of thoseweight/volume percents or more and that those variances can bespecifically used to create ranges for the ingredients of the presentinvention. For example, an ingredient weight/volume percent of 10% witha variance of ±20% means that the ingredient can have a weight/volumepercentage range of 8 to 12 w/v %.

Applicants specifically incorporate the entire contents of all citedreferences in this disclosure. Further, when an amount, concentration,or other value or parameter is given as either a range, preferred range,or a list of upper preferable values and lower preferable values, thisis to be understood as specifically disclosing all ranges formed fromany pair of any upper range limit or preferred value and any lower rangelimit or preferred value, regardless of whether ranges are separatelydisclosed. Where a range of numerical values is recited herein, unlessotherwise stated, the range is intended to include the endpointsthereof, and all integers and fractions within the range. It is notintended that the scope of the invention be limited to the specificvalues recited when defining a range.

Other embodiments of the present invention will be apparent to thoseskilled in the art from consideration of the present specification andpractice of the present invention disclosed herein. It is intended thatthe present specification and examples be considered as exemplary onlywith a true scope and spirit of the invention being indicated by thefollowing claims and equivalents thereof.

We claim:
 1. An ophthalmic emulsion, the emulsion comprising: waterforming an aqueous phase; oil forming an oil phase; a hydrophilicsurfactant having an HLB value of from 10 to 18; a hydrophobicsurfactant having an HLB value of from 1 to 6; a charged phospholipid;borate; a mucoadhesive galactomannan polymer; and a preservative,wherein the preservative is free of a benzalkonium chloride, wherein: i.the oil phase is in droplets within the aqueous phase and the dropletshave an average diameter that is no greater than about 1000 nm, but isat least 10 nm, wherein the average diameter is corresponding to 90% ofthe cumulative undersize distribution by volume measured using aMicrotrac S3500 Particle Size Analyzer (Software Version 10.3.1); andii. the borate and galactomannan polymer cooperatively act to form a gelupon instillation of the emulsion in an eye of an individual.
 2. Anemulsion according to claim 1 wherein the oil is a hydrocarbon selectedfrom mineral oil, paraffin oil and petrolatum.
 3. An emulsion accordingto claim 1 wherein the oil is at least 0.1 w/v % and no greater than 5w/v %, preferably at least 0.8 w/v % and no greater than 1.5 w/v % ofthe emulsion.
 4. An emulsion according to claim 1 wherein thehydrophilic surfactant is present in the emulsion in an amount that isat least 0.08 w/v % and is present in the emulsion in an amount that isno greater than 0.8 w/v %, preferably wherein the hydrophilic surfactantis present in the emulsion in an amount that is at least 0.14 w/v % andis present in the emulsion in an amount that is no greater than 0.44 w/v%.
 5. An emulsion according to claim 1 wherein the hydrophilicsurfactant is polyoxyethylene-40-stearate.
 6. An emulsion according toclaim 1 wherein the hydrophobic surfactant is present in the emulsion inan amount that is at least 0.11 w/v % and is present in the emulsion inan amount that is no greater than 2.0 w/v %, preferably wherein thehydrophobic surfactant is present in the emulsion in an amount that isat least 0.16 w/v % and is present in the emulsion in an amount that isno greater than 0.62 w/v %.
 7. An emulsion according to claim 1 whereinthe hydrophobic surfactant is a sorbitan tristearate.
 8. An emulsionaccording to claim 1 wherein the mucoadhesive galactomannan polymer isselected from the group consisting of guar and hydroxypropyl guar.
 9. Anemulsion according to claim 1 wherein the mucoadhesive galactomannanpolymer is present in the emulsion at a concentration of at least 0.01w/v %, but no greater than 1.0 w/v %, preferably of at least 0.01 w/v %,but no greater than 0.08 w/v %.
 10. An emulsion according to claim 1wherein the charged phospholipid is an anionic phospholipid nameddimyristoyl phosphatidylglycerol.
 11. An emulsion according to claim 1wherein the phospholipid is present in the emulsion in a concentrationfrom 0.05 to 7.0 percent by weight.
 12. An emulsion according to claim 1further comprising a borate/polyol buffer system.
 13. An emulsionaccording to claim 1, the preservative is a polymeric quaternaryammonium compound.
 14. An emulsion according to claim 1 wherein the oilphase is in droplets within the aqueous phase and the droplets have anaverage diameter that is no greater than 500 nm but is at least 100 nm,wherein the average diameter is corresponding to 90% of the cumulativeundersize distribution by volume measured using a Microtrac S3500Particle Size Analyzer (Software Version 10.3.1).
 15. A methodcomprising: instilling the emulsion of claim 1 into an eye of a mammal.16. A method according to claim 15 wherein the mammal is a human beingand the emulsion is instilled as drops from an eye dropper.
 17. A methodof forming an emulsion of claim 1 comprising: forming a first admixtureby mixing the oil and the surfactants at an elevated temperature to forman oil phase admixture; forming a second admixture by mixing the anionicphospholipid into purified water at an elevated temperature to form awater phase admixture; mixing the oil phase admixture and the waterphase admixture at an elevated temperature and subsequently homogenizingthe oil phase mixture with the water phase mixture to form an initialemulsion; and forming a third admixture by mixing the galactomannanpolymer with water and adjusting pH as needed to form a galactomannanpolymer slurry; and mixing the galactomannan polymer slurry with theinitial emulsion to form a polymer enhanced emulsion; and forming afourth admixture by mixing any combination of the following to form asalt solution: borate, polyol, preservative and any other ingredients;and mixing the salt solution with the enhanced emulsion followed by theaddition of a sufficient quantity (Q.S.) of water and pH adjustment.